Effect of Evolocumab on Progression of Coronary Atherosclerosis in Statin-Treated Patients: A Placebo-Controlled Intravascular Ultrasound Trial

The ‘GLobal Assessment of plaque reGression with a PCSK9 antibOdy as measured by intraVascular ultrasound’ (GLAGOV) trial demonstrated more LDL-c reduction, but also more regression of coronary atherosclerosis with a PCSK9 inhibitor op top of a statin, compared to statin monotherapy.

Using intravascular ultrasound (IVUS), prior studies showed that statins contribute to a slower progression or induction of regression of coronary disease, which were in proportion to the magnitude of LDL-c reduction. However, there has been no other LDL-lowering therapy that showed regression in an IVUS study.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors also show a substantial reduction in LDL-c levels, but the effect on progression was thus far unknown. This prompted the GLAGOV trial investigators to investigate the effect of the PCSK9 inhibitor evolocumab on coronary atherosclerosis. This was assessed using percent atheroma volume (PAV) measurements in individuals with coronary artery disease who were treated with statins and required angiography for clinical indication.

The phase III GLAGOV trial is double-blinded and placebo-controlled trial in which 968 patients from 32 different countries were enrolled, who presented 20-50% stenosis on angiography. Patients were randomized 1:1 for statin monotherapy or statin plus monthly evolocumab 420 mg for 18 months. Patients were prior to treatment and after treatment subjected to IVUS.

The results of the GLAGOV trial demonstrated after 18 months of statin monotherapy median LDL-c levels of 93 mg/dL and after evolocumab therapy 36,6 mg/dL. In contrast to monotherapy-treated patients, whom increased LDL-c with 3,9% from baseline, patients treated with evolocumab showed a 59,8% reduction in LDL-c from baseline.
This was accompanied by a 0,05% PAV increase for monotherapy-treated patients and a 0,95% PAV reduction for evolocumab-treated patients (P<0,001). This corresponded to a reduction of coronary atherosclerosis (based on PAV) in 47,3% of patients treated with monotherapy and in 64,3% of evolocumab-treated patients (P<0,001). Moreover, 52,7% of the monotherapy-treated had progression of coronary atherosclerosis, in contrast to only 35,7% of evolocumab-treated patients (P<0,001). A similar trend was observed for a subgroup of patients with baseline LDL-c levels below 70 mg/dL; PAV was reduced with 0,35% and 1,97% for monotherapy-treated and evolocumab-treated patients respectively (P<0,001) and the frequency of patients with regression of coronary atherosclerosis was 48% and 8,2% respectively. Even patients with baseline LDL-c levels of 20 mg/dL showed a similar PAV-reduction benefit with evolocumab combination therapy. None of the examined subgroups had enhanced benefit from the combination therapy compared to other patients, although patients with low non-HDL levels at baseline trended towards more benefit from evolocumab compared to patients with high non-HDL levels (P interaction = 0,09).
Furthermore, the number of adverse events and adverse clinical events were comparable between both groups, although slightly less evolocumab-treated patients experienced a first major cardiovascular event (12,2% versus 15,3% of monotherapy patients).

In conclusion, in addition to lower LDL-c levels with evolocumab on top of statins, this therapy also initiated regression of coronary atherosclerosis more and more often compared to statins alone. This benefit was also observed for patients with baseline LDL-c levels that were lower than guideline recommendations. In addition, no problems were observed regarding the safety of evolocumab in this trial, although the number of patients included in this trial were modest resulting in a limited power of the analyses.

This study has been published today in JAMA ((Nicholls S.J. et al, Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial).